Methods for relieving bronchial spasm with prostaglandin-f{11 and derivatives

ABSTRACT

Prostaglandin-F2 , 7-(3 Alpha ,5 Beta -dihydroxy-2-(3-hydroxy1-octenyl)cyclopentyl)-5-heptenoic acid, its esters, alkali metal salts, and amine salts provide potent and non-toxic compositions and methods for relieving bronchial spasm and facilitating breathing in warm-blooded animals. Administration by the oral inhalation route is particularly efficacious.

[ 1 Oct. 9, 1973 METHODS FOR RELIEVING BRONCHIAL 15 W HBQ ANP -E 4N DERIVATIVES [75] Inventor: Marvin E. Rosenthale, l-lavertown,

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: Dec. 2, 1971 [21] App]. No.: 204,304

[52] US. Cl. 424/305, 424/318 [51] -Int. Cl A6lk 27/00 [58] Field of Search 424/305, 318

[56] References .Cited OTHER PUBLICATIONS Pickles-Biol0gical Reviews-Vol. 42, (1967), pages Primary Examiner-Sam Rosen Att0mey-Vito Victor Bellino et a1.

[ ABSTRACT Prostaglandin-F 7-[3a,5B-dihydroxy-2-(3-hydroxyl-octenyl)cyclopentyl]-5-hepten0ic acid, its esters, alkali metal salts, and amine salts provide potent and nont ox i c .comgosjtiqns and methods for relieving bronchial spasm and facilitating breathing in warm-blooded animals. Administration by the oral inhalation route is particularly efficacious.

4 Claims, No Drawings METHODS FOR RELIEVING BRONCHIAL SPASM WITH PROSTAGLANDIN-F AND DERIVATIVES BACKGROUND OF THE INVENTION A number of compounds in a variety of combinations and dosage forms are currently available as bronchodilators, i.e., substances able to relax and smooth muscle of the bronchial tree and thus control spasm and facilitate breathing in conditions affecting animals, such as bronchial asthma, bronchitis, bronchietasis, pneumonia, emphysema, and the like. All of the bronchodilator preparations incorporate one or more of three basic types of compounds: (a) sympathomimetic (adrenergic) agents, (b) xanthine derivatives and (c) corticosteroids. These agents are frequently used in combination with anti-tussives, expectorants, mucolytics, and the like.

The sympathomimetic agents most often used are epinephrine, isoproterenol, phenylephrine and ephedrine. These adrenergic agents are most powerful and useful drugs in the relief of severe asthmatic spasm (status asthmaticus); however, as with other dilators they have untoward side effects. Some of the more undesirable of these are stimulation of the cardiovascular and central nervous system, hyperglycemic and tolerance (tachyphylaxis), which greatly reduces the effectiveness of these drugs.

The two xanthine derivatives most widely used are theophylline and aminophylline. Some of the problems associated with therapy with these drugs include variable oral absorption, cardiovascular effects and inability to achieve adequate levels without gastric irritation.

Many cases of asthma and status asthmaticus refractory to usual treatment methods are now controlled by the corticosteroids. However, long term treatment of asthma with steroids involves the risk of sodium retention, hypertension, ulcers, calcium loss from osseous structures and other well known side effects.

Thus, the agents presently available to the physician have a number of problems associated with their use, including toxicity, low activity (especially in the Xanthines), adverse effect on the cardiovascular system (especially in the sympathomimetics) and fluid retention or edema (with the corticosteroids). Thus, a definite need exists for means employing effective and well-tolerated bronchodilating agents.

The difficulty in finding such agents is'well known to those skilled in the art. It is a matter of common knowledge and experience, for example, that many compounds that relax smooth muscles are not bronchodilators by all common routes of administration (and especially by the aerosol route of administration). For example, for some obscure reason, ephedrine is a smooth muscle relaxant and is an orally active bronchodilator, but not by aerosol; epinephrine, also a smooth muscle relaxant, is used by aerosol but not orally. And aminophylline, a drug which can relax bronchial smooth muscle in vitro or by injection in vivo is inactive as a bronchodilator aerosol. In view of this it is surprising to find means which, even though characterized by smooth muscle relaxing activity, provide bronchodilation by injection, by oral administration and by administration via the aerosol route, possess high levels of activity, and are non-toxic.

In Belgian Pat. Nos. 711,025 and 736,977 there are disclosed means for accomplishing such salutory bronchodilating and bronchial spasm reducing effects by use of preparations containing certain prostaglandin compounds. Included among these prostaglandins are the compounds known in the art as PGF a and PGF; (1, which have the structural formulae PGFIia Pen,

is not useful as a bronchodilating and bronchial spasm reducing agent. To the contrary, it is a bronchoconstricting agent and is art recognized as such, as, for example, in Sweatman et al., Nature, 217, 69 (1968);

Bergstrom et al., Pharmacological Reviews, 20, No. l, I

p. 17 (1968); Anggard et al., Acta Physiol. Scand., 58, l (1963); and Berry et al., Brit. J. Pharmacol., 23, 201 (1964). In view of all this, it is truly surprising to find that prostaglandin-F 3 which possesses the identical side-chain unsaturation as the bronchoconstricting compound PGF, and which lacks the Sa-hydroxy configuration of PGF, a and PGE, is itself a potent bronchodilating agent which provides methods and compositions for producing bronchodilation and reducing bronchial spasm in warm-blooded animals. 1

SUMMARY OF THE INVENTION The invention sought to be patented in its process aspect resides in the concept of a method of relieving bronchial spasm and facilitating breathing in warmblooded animals which comprises administering to a warm-blooded animal in need thereof an amount sufficient to relieve bronchial spasm and facilitate breathing in said warm-blooded animal of a'composition comprising: (a) a compound of the formula OH OH wherein R is hydrogen, alkyl of from one up to about six carbon atoms, alkali metal, or a pharmacologically acceptable cation derived from ammonia or a basic amine; and (b) a pharmacologically acceptable inhalation carrier, in an amount sufficient to provide a composition administerable by the oral inhalation route.

DESCRIPTION OF THE PREFERRED EMBODIMENTS All of the compounds of formula I used in the compositions and methods of this invention can be conveniently prepared by methods known in the art. The compound of formula l where R is hydrogen, that is prostaglandin-F B can readily be prepared by reduction of the naturally occurring prostaglandin-E to give a mixture of PGF, and PGF; 3 followed by chromatographic separation. This method is described, for example, in Pike et al., J. Org. Chem., 34, 3552 1969). The esters of formula I (R is alkyl) are prepared by standard methods, such as'for example, by treating a solution of the free acids with diazomethane or other appropriate diazohydrocarbons, such as diazoethane, l-diazo-Z-ethylpentane, and the like. The alkali metal carboxylates of the invention can be prepared by mixing stoichiometrically equivalent amounts of the free acids of formula I, preferably in aqueous solution, with solutions of alkali metal bases, such as sodium, potassium, and lithium hydroxides or carbonates, and the like, then freeze drying the mixture to leave the product as a residue. The amine salts are prepared by mixing the free acids, preferably in solution, with a solution of the appropriate amine, in water, isopropanol, or the like, and freeze drying the mixture to leave the product as a residue.

The term alkyl of from about one to about six carbon atoms when used herein and in the appended claims includes straight and branched chain hydrocarbon radicals, illustrative members of which are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, nhexyl, 3-methylpentyl, 2,3-dimethylbutyl, and the like. Alkali metal includes, for example, sodium, potassium, lithium, and the like. A pharmacologically acceptable cation derived from ammonia or a basic amine contemplates the positively charged ammonium ion and analogous ions derived from organic nitrogenous bases strong enough to form such cations. Bases useful for the purpose of forming pharmacologically acceptable non-toxic addition salts of such compounds containing free carboxyl groups form a class whose limits are readily understood by those skilled in the art. Merely for illustration, they can be said to comprise, in cationic form, those of the formula:

wherein R, R and R independently, are hydrogen, alkyl of from about one to about six carbon atoms, cycloalkyl of from about three to about six carbon atoms, monocarbocyclicaryl of about six carbon atoms, monocarbocyclicarylalkyl of from about seven to about ll carbon atoms, hydroxyalkyl of from about one to about three carbon atoms, or monocarbocyclicarylhydroxyalkyl of from about seven to about 15 carbon atoms or, when taken together with the nitrogen atom to which they are attached, any two of R, R and R form part of a 5 to 6-membered heterocyclic ring containing carbon, hydrogen, oxygen, or nitrogen, said heterocyclic rings and said monocarbocyclicaryl groups being unsubstituted or monoor dialkyl substituted, said alkyl groups containing from about one to about six carbon atoms. Illustrative therefore of R groups comprising pharmacologically-acceptable cations derived from ammonia or a basic amine are ammonium, mono-, di-, and tri-methylammonium, mono-, diand triethylammonium, mono-, di-, and tripropylammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium cyclohexylammonium benzylammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1- methylpiperidinium, 4-ethylmorpholinium l-isopropylpyrrolidinium, l,4-dimethylpiperazinium, l-nbutylpiperidinium, Z-methylpiperidinium, l-ethyl-Z- methylpiperidinium, mono-, diand triethanolammonium, ethyldiethanolammonium, n-butylmonoethanolarnmonium, tris (hydroxymethyl)methylammonium, phenylmonoethanolammonium, and the like.

In practicing the method of the invention, the instant compositions can be administered in a variety of dosage forms, the oral route being used primarily for maintenance therapy while injectables tend to be more useful in acute emergency situations. Inhalation (aerosols and solution for nebulizers) seems to be somewhat faster acting than other oral forms but slower than injectables and this method combines the advantages of maintenance and moderately-acute stage therapy in one dosage unit.

The daily dose requirements vary with the particular compositions being employed, the severity of the symptoms being presented, and the animal being treated.

The dosage varies with the size of the animal. With large animals (about 70 kg. body weight), by the oral inhalation route, with for example a hand nebulizer or a pressurized aerosol dispenser the dose is from about 5 micrograms to about 100 micrograms, and preferably from about to about 50 micrograms, approximately every 4 hours, or as needed. By the oral ingestion route, the effective dose is from about 1 to about 20 mg., preferably from about 5 to about 10 mg. up to a total of about 40 mg. per day. By the intravenous route, the ordinarily effective dose is from about 50 micrograms to about 300 micrograms, preferably about 200 micrograms per day.

For unit dosages, the active ingredient can be compounded into any of the usual oral dosage forms including tablets, capsules and liquid preparations such as elixirs and suspensions containing various coloring, flavoring, stabilizing and flavor masking substances. For compounding oral dosage forms the active ingredient can be diluted with various tableting materials such as starches of various types, calcium carbonate, lactose, sucrose and dicalcium phosphate to simplify the tableting and capsulating process. A minor proportion of magnesium stearate is useful as a lubricant. In all cases, of course, the proportion of the active ingredient in said composition will be sufficient to impart bronchodilating activity thereto. This will range upward from about 0.0001 percent by weight of active ingredient in said composition.

For administration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute aqueous solution, preferably at concentrations of 9 about 1 part of medicament to from about 100 to 200 parts by weight of total solution. Entirely conventional additives may be employed to stabilize these solutions or to provide isotonic media, for example, sodium chloride, sodium citrate, citric acid, sodium bisulfite, and the like can be employed.

For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can also be used a dispersing agent such as oleyl alcohol. Suitable means to employ the aerosol inhalation therapy technique are described fully in U.S. Pat. Nos. 2,868,691 and 3,095,355, for example.

The following examples are given to illustrate the invention, but not in any way to limit its scope.

EXAMPLE 1 Anesthetized (Dial-urethane) guinea pigs were artificially respired at a constant positive air pressure (Starling miniature pump) and changes in tidal air during inspiration were recorded, according to the method of Rosenthale et al., Int. Arch. Pharmacol., 172, 91 (1968). The bronchoconstrictor agent acetylcholine was administered at doses of 10 to 40 meg/kg depending on each animal's sensitivity to this compound, and control responses to acetylcholine were thus established. Bronchoconstrictor agents raise the resistance of the lungs to inflation thereby decreasing the tidal air flow. Prostaglandin-F B was then administered either intravenously or by aerosol, and the animals were then challenged again with acetylcholine, and the degree of inhibition of bronchoconstriction by PGF2 B was thus determined.

Results Route Dose No. Pigs inhibition of PGF B Acetylcholine LV. l0 meg/kg 3 41 xv 100 meg/kg s 77 A.R. 0.027 rncg l 28 A.R. 0.27 mcg 2 42 A.R. 2.7 mcg 3 60 A.R. 27 mcg 2 90 Maximum effect 1-2 min. after drug.

'' l.V. (intravenous), dose administered as meg/kg; A.R. (aerosol), dose administered as total mcg per animal.

EXAMPLE 2 A composition is prepared comprising 1 part of 7- [3a,5B-dihydroxy-2-( 3-hydroxyl -octenyl)cyclopentyl]-5-heptenoic acid and 300 parts by weight of 0.06 M aqueous phosphate buffer. For administration to relieve bronchial spasm by oral inhalation with a hand nebulizer, in animals of from about 20 to about 80 kilograms body weight, three to five inhalations of the solution are used every 4 hours.

EXAMPLE 3 Tablets for oral use are prepared with the following formulations:

Milligrams 7-[ 3a,5/3dihydroxy-2- (3-hydroxyl octenyl) cyclopentyl ]-5-heptenoic acid 5 l0 Lactose 29 2 2 8 7 Magnesium stearate 3 3 300 300 One tablet containing either 5 or l0 mg. of active ingredient is administered to an animal of about kg. body weight suffering from bronchial spasm. Up to a total of about 40 mg. per day can be well tolerated in divided doses.

EXAMPLE 4 The procedure of U.S. Pat. No. 2,868,691 is used to prepare the instant compositions in selfipropelling dosage unit forms.

A suitable measured quantity of the medicament is mixed with, and dissolved in, a measured amount of the cosolvent. A stabilizer, if desired, is added. A measured quantity of the resulting solution is then introduced into an open container. The open container and its contents are then cooled, preferably to a temperature below the boiling point of the propellant to be employed. A temperature of 25F. is usually satisfactory. A measured quantity of the liquified propellant which also has been cooled below its boiling point is then introduced into the container and mixed with the solution already present. The quantities of the components introduced into the container are calculated to provide the desired concentration in each of the final compositions. Without permitting the temperature of the container and its contents to rise above the boiling point of the propellant, the container is sealed with a closure equipped with a suitable dispensing valve arrangement. Upon warming to room temperature the contents of the container are mixed by agitation of the container to insure complete solution of the medicament. The sealed container is then ready to dispense the composition and provide the medicament in aerosol form."

Nebulizing units each containing 15 ml. are filled according to the manipulative procedure described above with the following composition:

Percent 7-[3a,5Bdihydroxy-2- (3hydrcxyl -octenyl) cyclopentyH-S-heptenoic acid 0. l 5 Ethanol 3 4. 8 5 Dichlorotetrafluoroethane 40 Dichiorodifluoromethane 25 l These packages when adjusted to deliver 500 single oral inhalations provide a single dose of 45 micrograms. A single inhalation is administered to control an acute bronchial spasm. If necessary, after a full minute has elapsed, a second inhalation can be administered.

EXAMPLE An injectable unit dosage composition is prepared by dissolving 100 mg. of 7-[3a,5;3-dihydroxy-2-(3- hydroxyl-octenyl)cyclopentyl]-5-heptanoic acid in 30 ml. of 0.2 M sodium phosphate buffer, pH 7.4 and is made up to 100 ml. with distilled water. This solution of medicament, containing 1 rng./ml. of active ingredient (calculated as the free acid) is stored frozen at C. until thawed for sterile filtration. After sterile filtration through a 0.45 micron filter, 1 ml. aliquots are filled aseptically into sterile ampules. The ampules are flame sealed and the contents are frozen and stored at 20C. until needed.

The subject matter which applicant regards as his invention is particularly pointed out and distinctly claimed as follows:

l. A method of relieving bronchial spasm and facilitating breathing in warm-blooded animals which comprises administering to a warm-blooded animal in need thereof an amount sufficient to relieve bronchial spasm and facilitate breathing in said warm-blooded animal of a composition comprising:

a. a compound of the formula wherein R is hydrogen, alkyl of from one up to about six carbon atoms, alkali metal, or a pharmacologically acceptable cation derived from ammonia or a basic amine; and

b. a pharmacologically acceptable carrier.

2. A method as defined in claim 1 wherein said administration is effected by the oral inhalation route.

3. A method as defined in claim 2 wherein (a) is administered at from about 5 micrograms up to about 50 micrograms per dose.

4. A method as defined in claim 1 wherein said compound is 7-[3a,5B dihydroxy-2-( S-hydroxyl octenyl)cyclopentyl]-5-heptenoic acid. 

2. A method as defined in claim 1 wherein said administration is effected by the oral inhalation route.
 3. A method as defined in claim 2 wherein (a) is administered at from about 5 micrograms up to about 50 micrograms per dose.
 4. A method as defined in claim 1 wherein said compound is 7-(3 Alpha ,5 Beta -dihydroxy-2-(3-hydroxy-1-octenyl)cyclopentyl)-5-heptenoic acid. 